The mechanism whereby the allogeneic fetus avoids immune rejection during pregnancy is unknown. Until recently, it was thought that the implanted fetus escaped rejection either because it was antigenically immature, or because it was sequestered in an immunologically privileged site. Current evidence, however, suggests that the fetus and placenta actively suppress the alloreactive components of the maternal immune system. leading to a special case of peripheral tolerance. We propose to evaluate this possibility using a genetic approach in mice. These studies have implications for several reproductive disorders and autoimmune diseases, the mechanisms used by cancer cells to avoid immune surveillance, and may have applications in organ transplantation and the prevention of graft-versus-host disease. The aims of the proposal are as follows: l) Using known mouse mutations and blocking monoclona1 antibodies, we will evaluate the reproductive requirements for interleukin A and interleukin-10, two key cytokines that regulate the mode of T cell differentiation associated with pregnancy, as well as the requirements for Fas and CTLA-4, two factors required for peripheral tolerance. 2) We will generate transgenic mice that express ovalbumin on placental tissues, and then use these mice to study the T cell responses to placental antigens and the pathways of fetal antigen presentation to the maternal immune system. These studies will take advantage of genetic techniques and T cell receptor transgenic mice that have been previously used to study similar issues outside the placenta. 3) We will test whether diminished cytotoxic T cell activity towards the fetus is due to a specific inhibition of helper T cell function. These experiments will rely upon the ability of activating monoclonal antibodies towards CD40 expressed by antigen presenting cells to substitute for helper cell function in vivo. 4) We will take advantage of the ability of methyl-tryptophan to induce the immune rejection of allogeneic but not syngeneic concepti in order to isolate genes expressed by placental tissues that might induce maternal immune tolerance. Genes will be isolated by cDNA representational difference analysis and DNA microchip array analysis. and will be functionally evaluated by their ability to modulate tumor immunogenicity in vivo.